Depression is an illness that is poorly understood and treatments are only effective in a certain percentage of the population. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant medications. SSRIs act indirectly via 5HT receptors, including the 5HT1A receptor that couples to heterotrimeric G proteins. Regulators of G protein signaling (RGS) are a family of intracellular proteins that negatively modulate receptor-mediated G protein signaling. Using mutant mice we have identified a subset of 5HT1A receptors coupled to G?i2 and negatively regulated by RGS proteins that appear to mediate the beneficial actions of SSRIs. This led us to consider that RGS protein modulation of 5HT1A receptor signaling may play an important role in depression and so present a novel target for the treatment of depression. However, there are >20 mammalian RGS proteins and a general inhibitor will likely have a broad range of effects. In this proposal we seek to identify the specific RGS protein that modulates 5HT1A receptors and therefore controls behavioral responses to 5HT1A receptor activation related to mood disorders. The proposed work will use a combination of behavioral, biochemical and molecular biological approaches to provide knowledge of RGS proteins in serotonin signaling in animal models of depression and implicate RGS proteins as drug targets to promote the antidepressant actions of currently available SSRI's without enhancing their unwanted effects. PUBLIC HEALTH RELEVANCE: Depression is a poorly understood illness that affects approximately 10 million Americans. Moreover, treatments for depression are ineffective in a majority of patients. We have recently identified a family of intracellular proteins (RGS proteins) that appear to enhance the beneficial actions of selective serotonin reuptake inhibitors (SSRIs) which are the major drugs used for the treatment of depression. In this proposal we seek to identify the particular RGS protein(s) involved and so identify a novel target for treatment of depressive illness.